Preparation of 1-methylpiperidylmethanols



Patented Oct. 27, 1953 PREPARATION OF l-METHYLPIPERIDYL- METHANOLSRolland F. Feldkamp, Troy, N. Y., assignor to Sterling Drug Inc., NewYork, N. Y., a corporation of Delaware No Drawing. Application September12, 1951, Serial No. 246,339

4 Claims.

This invention relates to a process for the preparation of1-methylpiperidylmethanols.

My new. process comprises catalytically hydrogenating a loWer-alkylpyridinecarboxylate, N-methylating the resulting lower-alkylpiperidinecarboxylate by treating it with an excess of formaldehyde andcatalytically hydrogenating the reaction mixture, reducing the resultinglower-alkyl 1-methylpiperidinecarboxylate by heating with sodium and aloWer-alkanol, and isolating the 1-methylpiperidylmethanol thus formed.

Appropriate catalysts for the hydrogenation of the lower-alkylpyridinecarboxylate include palladium, platinum, nickel, and copperchromite. The lower-alkyl pyridinecarboxylate is preferably dissolved orsuspended in a liquid medium. Said liquid medium can be an aqueoussolution of an acid such as acetic acid or can be an organic solvent notvulnerable to attack by hydrogen, such as ethanol, dioxane, ether ormethylcyclohexane. The reaction is carried out in a closed vessel underelevated pressure at room temperature or above. The uptake of hydrogencan be measured by conventional methods, as by drop in pressure on thegauge, so that the completeness of hydrogenation of the pyridine nucleusis readily determined. When reduction is complete the catalyst isremoved by filtration. Although the loweralkyl piperidine carboxylatethus formed can be isolated if desired, before proceeding with theN-methylation step, such isolation is unnecessary. A preferredembodiment comprises the use of a supported palladium catalyst such aspalladium-on-charcoal in a. dilute acetic acid solution for the ringreduction. The palladiumon-charcoal catalyst can be formed in situ frompalladium chloride and charcoal. Hydrogenation is complete in a fewhours at room temperature and an initial hydrogen pressure of about 1000lbs. per sq. in.

The intermediate alkyl piperidinecarboxylate, which need not be isolatedbut can simply be separated from the spent catalyst used for the ringreduction, is then N-methylated by addition of formaldehyde and furtherhydrogenation in the presence of a catalyst such as nickel, platinum orpalladium. A preferred catalyst is a supported palladium catalyst suchas palladium-on-charcoal. The N-methylated lower-alkylpiperidinecarboxylate is produced in good yield and is easily isolated.If an acetic acid solution is the medium employed the isolation isaccomplished by neutralization of the acid with a strong base,extraction and distillation of the lower-alkyll-methylpiperidinecarboxylate. If the same catalyst is used for the ringreduction and the N -methylation, the operations are simplified sincethe intermediate alkyl piperidine carboxylate need not be separated fromthe catalyst used for the ring reduction; formaldehyde is simply addedafter the ring reduction is complete and the process continued. Apreferred method comprises the use of a palladium-on-charcoal' catalystfor both the ring reduction and the N -methylation; enough gatalyst isadded initially to carry out both reac- The reduction of the carbalkoxygroup is carried out by heating the lower-alkyll-methylpiperidinecarboxylate with metallic sodium and a lower alkanol.The reaction mixture is preferably diluted with an inert organic solventsuch as toluene, benzene or petroleum ether in order that the reactionbetween the sodium and the alcohol will :be retarded. Any lower-alkanolcontaining 1-8 carbon atoms can be used, although the lowest members,methyl and ethyl alcohol, are not to be recommended because the yieldsobtained are poor probably due to their relatively high reactivitytowards sodium. An alcohol containing about 6 carbon atoms is preferredand 2-methylpentanol-4 has been found particularly useful. Aftersuflicient time has been allowed for the reduction, the reaction mixtureis hydrolyzed by addition of water. The desiredl-methylpiperidylmethanol then can be isolated from the organic layerand purified by distillation.

As starting materials any lower-alkyl pyridinecarboxylate can be used.The lower-alkyl group is carried through the reactions unchanged and isremoved in the form of a lower-alkanol during reduction of thelower-alkyl l-methylpiperidinecarboxylate to thel-methylpiperidylmethanol. For practical purposes the esters employedare preferably methyl or ethyl esters.

When the starting material is an alkyl nicotinate (alkyl S-pyridinecarboxylate), l-methyl-v 3-piperidylmethanol is obtained in the form ofa liquid having a refractive index at 25 C. for sodi-. um light of about1.4765, which forms the following derivatives: hydrochloride, M. P.about 135.5- 140 C.; methiodide, M. P. about 2l5.5-216.5 C.; and acetatemethiodide, M. P. about 130-131 C.

A method has been described [Sandborn and Marvel, J. Am. Chem. Soc. 50,563-7 '(1928) Renshaw et a1., ibid. 61, 638-40 (1939)] which comprisesreduction of an ethyl pyridinecarboxylate with sodium in ethyl alcohol,and N-methylation with a methyl halide. This process was assumed bythese investigators to give an N-methylpiperidylmethanol. For example,Sand-born and Marvel reduced ethyl nicotinate with sodium in ethylalcohol and N-methylated the product thus obtained with methyl iodide.The authors assumed that their final product wasl-methyl-3-piperidylmethanol. However it was not the same substanceasthatpreparedby my newprocess. This distinction is proved by thefollowing facts:

Ethyl nicotinate was reduced with sodium in alcohol according to thedirections of Sendborn and Marvel. The supposed 3-piperidylmethanol thusobtained was N-methylatedwvi-th formaldehyde and formic acid. Theresulting product, supposedly 1-methyl-3-piperidylmethanol, differedsignificantly in its chemical and :physical properties from thatprepared by way of my new process. The following table shows therespective physical properties, where 'thecolumnsrrelate to products asfollows:

I: Products prepared by sodium in alcohol reduction of ethyl nicotinate2nd N-methylation withformaldehyde and formicacid.

II: Reported by LSandborn and Marvel.

III: Product prepared by new'process.

pared readily by reaction of the N-methylpiperidinemethanol with theacid halide of a carboxylic acid or with an acid anhydride.Alternatively, and in case the ester desired is derived from an acidwhich does not conveniently form an acid halide, the=l-.methylpip.eridylmethanol ca be meatedaviththe free acid inia'ninert-solvent, preferably in the presence of an acid catalyst, withmeans for removing the water formed in the reaction. A convenient methodof carrying out this alternative procedure involves prolonged heating ofthe N-methylpiperidylmethanol with 11 III Boiling .point tantrum;

-113-11-5 (17 Inmz) 0.9649. l95-I96'C.

The product .1 was found :to absorb bromine and to take up hydrogen inthe presence ofa catalyst. Catalytic hydrogenation .Of 1 produced aliquid having the refractive .index,:n =1.4766; this is in :excellent:agreement :with the refractive index of product III. Thediphenylacetate hydrochloride .of LM. 1?. 169-175 .C., wasalsorcatalytically hydrogenated and :a product, :P. 195 1-96" 0., wasobtained which ;did 'not depress the :melting point of '.thediphenylacetate hydrochloride of III, .M. -P. l95-l96 0., uponadmixture. This demonstrates that the :product .of Sandborn and Marvelpossessed :nnclear unsaturation and was notil-methyl-B+piperidylmethanol as reported.

Further proof of the inopera-tiveness of the process of Sandborn andMarvel was-obtained by a comparison of the melting points of derivativesof ;l-methyl-.3-piperidylmethanol and l-methyl- 2-piperidylmethanol, asprepared by -my=new synthesis, with :those reported .by Benshaw et al.,J. .Chem.;-So'c. '61,- 639 (1939) ,who prepared what were presumed-to bel-anethyl-B-;oiperidyl-methanol and l-rmethyl-Z-piperidylmethanol ?by'the methodof 'Sandborn and Marvel. The following table shows a distinctdiscrepancy in melting points.

Renshaw et al. New'metho'd 1M. P. C. P.C.

l-metbyl-E-piperidylmethanolmethil40.-5'142 215.5216.'5.

odi e.

l-methyl-3-piperidylmethyl acetate 134-135 130-131.

methiodide.

l-rr.ethyl-2-piperidylmethanol methi- 275-280 (dec .over 300.

odide.

l-methyl-2 piperidy1methyl acetate 126. 5-128..5, 145-146.

methiodide.

A number of esters of the three isomeric N- methylpiperidinemethanolshave been prepared, certain individualsof which possess valuableantispas'modic properties. The esters can be pretains a thiophene'nuoleus'which is sensitive to acid-halide-formingreagents.

The esters are conveniently isolated and "char acterized in the form ofacid-addition salts and quaternary ammonium salts. I 'he-following tablediscloses a number of such esters and 'their melting-points.

Melting Compound p m ,.-o;-

1. .1-1nethy2apiperidylmethyl acetate methio'dide. -146 2..1-methyl-3-piperidylemthyl acetate methiodide. 130-131 fill-methylpiperidylmethyl acetate hydrochlcri 167-168 5 4.LmethYLB-pipetidylmethyl'benzoateihydrochloride .177-178 5.l-methyl-3-piperid-ylmethyl benzoate methiodide 1%..5-197 6.l-methyl-Ii-piperidylmethyl 'nicotinate dihydrochloride-.monohydrate. fMum. 147-149 7 13 piperidylmethyl 2-.thenoate hydrochlo- 152-153 8 perlmethylbenzilatehydrochloride. 2115-220 9. l-methylpipcridylmetliylhenzilate methohromidc. 227. 5-230 I0.'l-methyl=3-piperiilylmethyl phenYl-tZ-thienyhacetate hydtochl0ride174-175. 5 11.-lrmethyl=3rpiperidylmethyl.pheny thienyDacetate'nethiodide 153.5-155 l2. l-methyl-B-piperi ethyl d-hydroxyrphenylbutaooate methiodide 158-162 13. l-methyl-3-pipelidylmethyl3-hydroxy-2-phcnylbutanoate methobromide 187-190 14..l-methyleA-piperidylmethylacetate methiodide... 149. 5-151. 5

compounds Nos. 10 and 11 are described and claimed :in my priorapplication, Serial No. 124,489, filed October 29,, 1949, .now U. S.Patent 2,533,002.

Compounds Nos. 12 and 13 are described and claimed in my priorapplication, Serial No. 124,490, filed October 2-9, 1949, now U. S.Patent 2,533,003.

The following examples will further illustrate my invention.

'EXANIPLE 1 (a) Ethyl 1emethylpiperidinee3 carbo:nylate. Ethylnicotinate (453.5.g.,.3.moles) was suspended in 500 cc. of water andtreated with 343 .cc. .(6.

moles) of glacial acetic acid. The solution was diluted to 1500 cc. withwater and placed in a rocking bomb hydrogenator with 7.5 g. of Adamsplatinum oxide catalyst. Slightly over the theoretical amount ofhydrogen was. absorbed in four hours at room temperature. The initialpressure of hydrogen was 1200 lbs. per sq. in., and the pressuregradually dropped to 200 lbs. per sq. in. at the end of thehydrogenation. The catalyst was removed by filtration and the filtratereturned to the hydrogenator with 300 cc. of 36% formaldehyde (3.6moles) and 30 g. of palladium catalyst freshly prepared from 3 g. ofpalladium chloride and 27 g. of activated charcoal. Absorption ofhydrogen proceeded very rapidly at room temperature and was completewithin two hours. The catalyst was removed by filtration through aBiichner funnel. The clear filtrate was cooled to C. and slowly treatedwith 300 g. of potassium hydroxide pellets and 300 cc. of

% potassium hydroxide solution. The liberated basic ester was extractedwith ether and the combined extract dried over anhydrous magnesiumsulfate. After filtration and removal of solvent, the residual oil wasdistilled under reduced pressure, giving 389.7 g. of ethyl 1-methylpiperidine-3-carboxylate, B. P. 98-995 C. at 17- 18mm. (76%) n =1.4474.

(b) 1-methyl-3-piperidylmethano-Z. Freshly cut sodium metal (214.5 g.,9.33 moles) was placed in a 5 liter flask fitted with a stirrer,dropping funnel, condenser, and calcium chloride tube. The sodium wascovered with a sufficient part of 1900 cc. of dry toluene and themixture heated to refluxing. The molten sodium and toluene wereefficiently stirred and heated at a low reflux rate While a solution of389.7 g. (2.215 moles) of ethyl 1-methylpiperidine-3-carboxylate in 482g. (4.66 moles) of 2-methylpentanol-4 and the remaining toluene wasadded slowly. The addition was made over a period of four hours withjust sufficient external heating to maintain refluxing. When theaddition was complete, the reaction mixture was stirred and refluxed forone-half hour longer and then allowed to cool to about 80 C. A smallamount of dispersed sodium was disregarded and the mixture slowlyhydrolyzed with 600 cc. of water. Care should be taken to preventoverheating and excessive foaming during this process. The warmhydrolysis mixture was immediately transferred to a separatory funnel,the toluene layer removed and the aqueous layer further extracted withthe same solvent. The combined extract was dried over anhydrousmagnesium sulfate. After filtration the toluene was removed bydistillation at atmospheric pressure, and the 2-methylpentanol-4 wasdistilled oil at partially reduced pressure. The residual oil distilledat 112-114 C. at 15 mm. pressure, giving 237.1 g. of1-methyl-3-piperidylmethanol as a straw-colored oil; n =1.4752 (82.8%).

A sample of 1-methyl-3-piperidylmethanol was converted to itshydrochloride by the action of dry hydrogen chlorid on an anhydrousether solution of the basic alcohol. The hydrochloride had the m. p.135.5-140 C., and when converted back to the free basic alcohol by theaddition of.

alkali gave a sample of'1-methyl-3-piperidylmethanol having n =1.4765.

An Z.Calcd. for C7H1sNO: C, 65.0; H, 11.70; N, 10.82. Found: C, 64.74;H, 11.48; N. 10.90.

(c) Methz'odide of 1-methyZ-3-piperidylmethanol.--A solution of 2.58 g.of l-methyl-3-piperidylmethanol and 5.67 g. of. methyl iodide in 25 cc.

of anhydrous ethyl alcohol was warmed for several hours on a steam bath.Upon cooling, a precipitat formed which was collected by filtrationgiving 5.5 g. of solid, M. P. 204-208 C. (dec.). Recrystallization ofthis material from ethyl alcohol gave 4.5 g. of the methiodide ofl-methyl- 3-piperidylmethanol, M. P. 215.5-2165 C.

Anal.Calcd. for C8H18INOI C, 35.43; H, 6.69; I, 46.81. Found: C, 35.31;H, 6.56; I, 46.80.

(d) 1-methyl-3-piperidylmethyl acetate methiodide.-A mixture of 17.4 g.of 1-methyl-3-piperidylmethanol methiodide and 61 g. of acetic anhydridewas refluxed for one-half hour. The excess acetic anhydride was removedin vacuo and the crystalline residue was stirred with an etherethanolmixture. The solid was collected by filtration and amounted to 19.6 g.(91%), M. P. -120 C. Recrystallization of this solid from anether-ethanol mixture gave a sample of 1 methyl 3 piperidylmethylacetate methiodide, M. P. 131 C.

AnaZ.-Calcd. for C10H20INO2: C, 38.35 H, 6.44; I, 40.53. Found: C,38.58; H, 6.56; I, 40.35.

EXAMPLE 2 (a) Ethyl 1 methylpiperidine-4-carboarylate was prepared by amethod similar to that-described in Example 1, part (a). Ethyl pyridine-4-carboxylate (44.85 g.) was hydrogenated using 0.75 g. of Adamsplatinum oxide catalyst in 34 cc. of glacial acetic acid and cc. ofwater. The intermediate ethyl piperidyl-4-carboxylate, not isolated, wasreacted with 30 cc. of formaldehyde in the presence of hydrogen andpalladium-oncharcoal catalyst (prepared from 0.3 g. of palladiumchloride and 0.3 g. of charcoal). The product, prepared byneutralization of the reaction mixture with 80 cc. of 40% potassiumhydroxide solution and extraction, was distilled in vacuo to give 38.8g. (76%) of ethyl l-methylpiperidine-4-carboxylate, B. P. 94 C. (12 mm.)n =1.4470.

(b) 1-methyl-4-piperidlymethanol was prepared by a method similar tothat described in Example 1, part (b) from the reaction of 38.8 g. ofethyl 1methylpiperidine-4-carboxylate, 20.9 g. of sodium and 46.8 g. of2-methylpentanol-4 in cc. of toluene. The product was distilled in vacuoto give 25.6 g. (87%) of 1-methyl-4- piperidylmethanol, B. P. 110-111 C.(10 mm.); n =1.4737. A redistillation gave 18.3 g. of 1-methyl-4-piperidylmethanol, B. P. 116 C. (16 mm.); n =l.4750.

Anal.-Calcd. for C7H15NO: N, 10.82. Found: N, 10.73.

The hydrochloride of l-methyll-piperidylmethanol formed byneutralization of the base with hydrochloric acid had the M. P.143.5-145.5 C. after recrystallization from alcohol.

(0) Methiodide of 1-methyZ-4-piperidylmethan0Z.A solution of 3.88 g. of1-methyl-4-piperidylmethanol and 5.78 g. of methyliodide in 50 cc. ofanhydrous ethyl alcohol was warmed for several hours on a steam bath.Upon cooling, a precipitate formed which was collected by filtrationgiving 5.5 g. (67%) of the methiodide of 1- methyl-4-piperidylmethanol,M. P. 204.5205.5 C.-

AnaZ.Calcd. for CsHrsINOZ C, 35.43; H. 6.69; I, 46.81. Found: C, 35.55;H, 6.59; I, 46.60.

(d) 1-methyl-4-piperidylmethyl acetate methz'odz'de.-A mixture of 6.5 g.of l-methyl-4-piperidylmethanol methiodide and 24.5 g. of aceticanhydride was refluxed for one-half hour. The excess acetic anhydridewas removed in vacuo and the crystalline residue was stirred with anether-ethanol mixture. The solid was cooled by filtration and amountedto 5.9 'g., M. !P. 150:5-3515" Recrystallization of this solid from anether-ethanol mixture gave .a sample of -1-'methyl-4-piperidy1methy1acetate methiodide, M. R 1495-1515 C.

Anal-@alcd. for CioHroINOz: C, 38.35; 51,644; I, 40.53. Found: C, 38.30;H, 6.36; I, 40130.

'pared' f-rom 0.26 g. of palladium chloride and-0.26

g. of charcoal). The product, prepared by neutralization of the reactionmixture with 72.5 cc. of 40% potassium hydroxide solution andextraction,was distilled invacuo to give 36;? g. (83%) of ethyl1-methylpiperidin'e2-carboxylate, B. P. 90-"9'5" "C. (16 mm.); n=1.4487.

Anal-Calm. for Gilly/N02: N, 8.21. Found:

(1)) i-methyl- 2 -piperidylmethanol was prepared by a method similar tothat described in Example 1, part ('5) from the reaction of 32 g.

of "ethyl 'l-methylpiperidine-Q carboxylate, 17.2

grof sodium'and 38.7 g. of 2-methylpentanol-4 in 175 cc. of toluene. Theproduct was distilled "in vacuo to give 22.? g. of liquid with nld'll'l. A 'redi'stillation gave 9.9 g. of 1-methyl-2-piperidylmethanol,B. P.'90'92 C. mm.)

AnaL-Calcd. for Cal-N0 2 C, 65.0; 11.70; N, 10.82. Found: C, 64.71; H,11.79; N, 10.83.

The hydrochloride of 1-methyl-2-piperidylmethanol formed byneutralization of the base with hydrochloric acid was very hygroscopicand no product with a definite melting point could be obtained.

(0) M ethiodide of 1-methyZ-2-piperidylmethanoL-A solution of 3.88 g. of1-methyl-2-piperidylmethanol and 5.78 g. of methyl iodide in 50 cc. ofanhydrous ethyl alcohol was warmed .ior several hours on a steam bath.The methiodide of .1.-.methyl-2-piperidylmethanol isolated from thisreaction was recrystallized from alcohol and had a M. P. above 300 C.

Anal.Calcd. for CsHmINO: C, 35.43; H, 6.69; I, 46.81. :Found: C, 35.46;H, 6.71; I, 46.45.

((1 1-methylZ-piper-idylmethyl acetate methiodide.-A mixture of 6.7 g.of l-methyl-Z-piperidylmethanol methiodide and 25.4 g. of aceticanhydride was refluxed for one-half hour. The excess acetic anhydridewas removed in vacuo and the crystalline residue was stirred with anetherethanol mixture. The solid was collected by fil tration'an'damounted to 7.9 g., M. P. -123" C. Recrystallization of the solid froman ether-ethanol mixture gave a sample of l-methyl-Z-piperidylmethylacetate methiodide, M. P. 146.5 C.

v.imiZ.---Calcd. for CioI-IzoINOZ C, 38.35; H, 6.44; I, 40:53.Found:'C,.38.33; .H, 6.32; I, 40.15.

Nicotinic acid (123.1 g.) was-added over .a. :period of fifteen minutesto 580 m1. of thionyl chloride with stirring. The mixture was refluxedfor -fours hours, concentrated in vacuo (33 -C 120 mm), and 300 .ml. ofabsolute alcohol was added dropwise over a period of fifty minutes. Thesolution was refluxed for thirty minutes, concentrated in vacuo, and theresidue (205 .g. containing ethyl =nicotinate) was dissolved in .150 ml.of hot water and stirred with 15 ;g. of activated charcoal to decolorizethe solution. The solution was filtered and to the filtrate were added149.6 ,g. of sodium acetate, 220 ml. of acetic acid, .30 g. of charcoaland 2.3 g. of ,palladium chloride, and the mixture was shakenin arocking-bomb hydrogenator at room temperature in an atmosphere ofhydrogen at .1000 lbs. per sq. in. pressure. Hydrogenation was completein eight hours. The hydrogenator was opened, 100 ml. of .formaldehydewas added, and the mixture was again shaken .for one and .one half hoursunder hydrogen .at 725 lbs. persqgm. The mixture was then filteredthrough a .fil'ter aid, thefiltrate was cooled to 10 C. and .neutral-.ized with stirring with 435ml. of 35% sodium hydroxide solution. Themixture was extracted several times with ether, the ether solution wasdried over anhydrous calcium sulfate and concentrated. The residue wasdistilled and the fraction boiling at 68 'C. (0.1 mm.) was cdllected,giving 126.5 g. of ethyl lemethylpiperidine-B- carboxylate, refractiveindex n5 1.4468.

A mixture of :151.2-g.'of=ethy1 .nicotinate, .115 ml. of glacial aceticacid, 167 ml. of water, 2.3 g. if palladium chloride and 30 g. ofcharcoal was shaken for fifteen hours in a rocking-bomb hydrogenator atroom temperature underhydrogen at 1000 lbs. per sq. in. The hydrogenatorwas then opened, 10.0 ml. of 36% formaldehyde was added and the mixturewas shaken for one and one-half hours :under hydrogen at 750 lbs. persq, in. The mixture was filtered through a filter aid, the :filtrate wassaturated with 500 g. of sodium chloride, covered with 300- ml. ofether, cooled to 0 C., and ml. of 38% sodium hydroxide was added. Theether layer was .sepa rated and the aqueous layer iurther extracted withether. The combined ether extracts were dried over anhydrous calciumsulfate and concentrated. The residue was distilled in vacuo and thefractionboiling at 75 C. (0.5 mm.-.) was collected,.giving 150.5 g. ofethyl 1-methylpiperidine-3-carboxy1ate, refractive index Thisapplication is a continuation-human or my copencling application, SerialNo. 122366 filed October 19, 1949, now abandoned.

I claim:

1. The process for preparing a l-methylpiperidylmethanol which comprisescatalytically ihydrogenating a lower-alkyl pyridinec'arboxylate using.a-catalyst selected from the group consisting of palladium, platinum,nickel and copper chromite, treating the resulting lower-alkylpiperidinecarboxylate with .an excesspf formaldehyde in 'thejpresence ofhydrogen and a cats.-

lyst selected from the group consisting of palladium, platinum andnickel, heating the resulting lower-alkyl'l-methylpiperi'dinecarboxylate with sodium and .a lower-alkanol having.from 3 8 car-- bon atoms, and isolating the resultingl-methylpiperidylmethanol.

2. The process for preparing a l-methylpiperidylmethanol which comprisescatalytically hydrogenating a lower-alkyl pyridinecarboxylate using apalladium catalyst, treating the resulting lower-alkylpiperidinecarboxylate with an excess of formaldehyde in the presence ofhydrogen and a palladium catalyst, heating the resulting loweralkyl1-methylpiperidinecarboxylate with sodium and a lower-alkanol havingfrom 3-8 carbon atoms, and isolating the resulting1-methylpiperidylmethanol.

3. The process for preparing a l-methyl piperidylmethanol whichcomprises catalytically hydrogenating a lower-alkyl pyridinecarboxylateusing a palladium catalyst, treating the resulting lower-alkylpiperidinecarboxylate with an excess of formaldehyde in the presence ofhydrogen and a palladium catalyst, heating the resulting loweralkyl1-methylpiperidinecarboxylate with sodium and Z-methylpentanol-, andisolating the resulting 1-methylpiperidylinethanol.

4. The process for preparing 1-methyl-3- piperidylmethanol whichcomprises catalytically hydrogenating a lower-alkyl nicotinate with apalladium catalyst, treating the resulting loweralkyl'3-piperidinecarboxylate with an excess of formaldehyde in the presenceof hydrogen and a palladium catalyst, heating the resulting lower- 10alkyl 1 methyl-3-piperidinecarboxylate with sodium and2-methylpentanol-4, and isolating the resulting1-methyl-3-piperidylmethanol.

ROLLAND F. FELDKAMP.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 1,659,666 Sohirmacher et al. Dec. 18, 1928 2,229,523 Walterset a1 Jan. 21, 1941 2,477,937 Paul et a1 Aug. 2, 1949 2,533,002 FeldkampDec. 5, 1950 2,533,003 Feldkamp Dec. 5, i950 FOREIGN PATENTS NumberCountry Date 441,122 Great Britain of 1936 717,712 France Jan. 13, 1932OTHER REFERENCES Marvel et al., Jour. Amer. Chem. Soc, vol. 51, pp.915-917 (1929).

Ford-Moore, Jour. Chem. Soc. (London) pp. -60 (1947).

Lands, Jour. Pharm. and Exp. Thera, vol. 102, #4, pp. 222, 227 (1951).

Sandborn et al., Jour. Amer. Chem. Soc., vol. 50, pp. 563-567 (1928).

Sauer et al., Chem. Abst., vol. 32 (1938) pp. 2532-2533.

1. THE PROCESS FOR PREPARING A 1-METHYLPIPERIDYLMETHANOL WHICH COMPRISES CATALYTICALLY HYDROGENATING A LOWER-ALKYL PYRIDINECARBOXYLATE USING A CATALYST SELECTED FROM THE GROUP CONSISTING OF PALLADIUM, PLATINUM, NICKEL AND COPPER CHROMITE, TREATING THE RESULTING LOWER-ALKYL PIPERIDINECARBOXYLATE WITH AN EXCESS OF FORMALDEHYDE IN THE PRESENCE OF HYDROGEN AND A CATALYST SELECTED FROM THE GROUP CONSISTING OF PALLADIUM, PLATINUM AND NICKEL, HEATING THE RESULTING LOWER-ALKYL 1-METHYLPIPERIDINECARBOXYLATE WITH SODIUM AND A LOWER-ALKANOL HAVING FROM 3-8 CARBON ATOMS, AND ISOLATING THE RESULTING 1-METHYLPIPERIDYLMETHANOL. 